PROJECT SUMMARY The complexity and multifactorial nature of Alzheimer's disease (AD) pose unique challenges for mechanistic studies and developing therapies. Age is the number one risk factor for AD, with imaging and biomarker data suggesting that the pathophysiological processes of AD begin more than a decade prior to the clinical diagnosis of dementia. Apolipoprotein (apo) E4 is the major genetic risk factor for AD, which also lowers the age of onset of AD in a gene dose-dependent manner. In most clinical studies, apoE4 carriers account for 60? 75% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Longitudinal studies in humans demonstrate that apoE4's detrimental effect on cognition depends on age and occurs before typical signs of AD arise. A challenge in AD research is to fully understand how the multiple etiologies, including apoE4, and age-related prodromal processes interactively contribute to the pathophysiology of AD. This proposal builds on three novel findings from our recent studies of mouse models. First, expression of apoE4 in female knock-in (KI) mice causes age-dependent impairment of GABAergic interneurons in the hilus of the hippocampus, which correlates with the severity of learning and memory deficits. Second, in vivo local field potential (LFP) recordings throughout the hippocampal circuit shows that compared to aged female apoE3-KI mice, aged female apoE4-KI mice have fewer sharp wave ripple (SWR) events?hippocampal network events critical for memory replay and consolidation?and have significantly reduced slow gamma activity during SWRs (see Preliminary Studies), which coordinates SWRs. Third, although most female apoE4- KI mice develop learning and memory deficits by 20 months of age, some of them (~25%) remain cognitively normal, similar to the proportion of apoE4/4 carriers who do not develop AD by 85 years of age. Understanding the neuronal and network mechanisms that differentiate the susceptible (pathological aging) and resistant (normal aging) groups of apoE4-KI mice might allow for the development of strategies to prevent or delay the disease in people at risk for AD. This proposal aims (1) to determine the effects of aging on apoE4 disruption of hippocampal network activity underlying memory replay and its relationship with GABAergic interneuron loss and cognitive decline in mice, (2) to explore whether apoE4 disruption of hippocampal network activity underlying memory replay occurs early and predicts the conversion of normal aging to AD-related pathological aging late in life in mice, and (3) to determine whether, during aging, persistent normal hippocampal network activity underlying memory replay predicts tenaciously normal cognition (normal aging) in apoE4-KI mice. The outcomes of the proposed studies will shed light on the interactive roles of apoE4 and aging in AD pathogenesis and could identify functional biomarkers capable of predicting the conversion of normal aging to AD-related pathological aging.